IMPROvE-CED Trial: Intracoronary Autologous CD34+ Cell Therapy for Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Arteries.

BACKGROUND: Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. METHODS: Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×105 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. RESULTS: Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [-18.0 to 32.4] to 57.6 [16.3-98.3]%; P=0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P=0.00018), and sublingual nitroglycerin use/day (1 [0.4-3.5] to 0 [0-1], Wilcoxon signed-rank test, P=0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. CONCLUSIONS: A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03471611.

Right heart catheterization predictors of symptomatic improvement in patients undergoing transcatheter tricuspid valve edge-to-edge repair.

BACKGROUND: Transcatheter tricuspid valve edge-to-edge repair (TTEER) is associated with improvement in outcomes for symptomatic patients with severe tricuspid regurgitation (TR). However, reliable predictors for clinical success are not yet fully defined. This study aims to describe right heart catheterization (RHC) findings in patients referred for TTEER and identify hemodynamic characteristics of patients who experience immediate symptomatic improvement following successful TR intervention. METHODS: Patients who underwent TTEER and had a separate RHC within the preceding 6 months were included. Hemodynamic tracings from the RHC and TTEER procedures were reviewed and recorded. Clinical success was defined as a successful device implant with at least 1-grade of TR reduction and improvement in NYHA class by 1 or more grades on 30-day echocardiogram and clinical follow-up. RESULTS: Thirteen patients underwent an RHC within 6 months of TTEER procedure (median age 76 years [IQR: 73-80]). All patients were on a stable dose of loop diuretics. Baseline right atrial pressure was severely elevated (mean 19 mmHg [IQR: 9-24 mmHg]) with prominent CV waves. Median pulmonary capillary wedge pressure (PCWP) was 20 mmHg (IQR: 14-22) and 70% of patients had a mean PCWP > 15 mmHg at rest. Median PCWP CV-wave was 34 mmHg (IQR: 23-42). Higher PCWP CV-wave height (40 mmHg [IQR 33-43] versus 18 mmHg [IQR 17-31]) was associated with lower likelihood of clinical success (OR 0.83, 95% CI: 0.35-0.97, p = 0.04). CONCLUSIONS: Inclusion of invasive hemodynamics as part of pre-TTEER evaluation may allow for improved TR phenotyping and patient selection. Patients with a large left atrial CV wave on resting RHC were less likely to experience immediate symptomatic improvement despite procedural success with TTEER.

Predictors of hemodynamic response to mitral transcatheter edge-to-edge repair.

BACKGROUND: Improvement in left atrial pressure (LAP) during transcatheter edge-to-edge repair (TEER) is associated with improved outcomes. We sought to investigate the predictors of optimal hemodynamic response to TEER. METHODS: We identified patients who underwent TEER at Mayo Clinic between May 2014 and February 2022. Patients with missing LAP data, an aborted procedure, and those undergoing a concomitant tricuspid TEER were excluded. We performed a logistic regression analysis to identify predictors of optimal hemodynamic response to TEER (defined as LAP ≤ 15 mmHg). RESULTS: A total of 473 patients were included (Mean age 78.5 ± 9.4 years, 67.2% males). Overall, 195 (41.2%) achieved an optimal hemodynamic response after TEER. Patients who did not achieve an optimal response had higher baseline LAP (20.0 [17-25] vs. 15.0 [12-18] mmHg, p < 0.001), higher prevalence of AF (68.3% vs. 55.9%, p = 0.006), functional MR (47.5% vs. 35.9%, p = 0.009), annular calcification (41% vs. 29.2%, p = 0.02), lower left ventricular EF (55% vs. 58%, p = 0.02), and more frequent postprocedural severe MR (11.9% vs. 5.1%, p = 0.02) and elevated mitral gradient >5 mmHg (30.6% vs. 14.4%, p < 0.001). In the multivariate logistic regression analysis, AF (OR = 0.58; 95% CI = 0.35-0.96; p = 0.03), baseline LAP (OR = 0.80; 95% CI = 0.75-0.84; p < 0.001) and postprocedural mitral gradient <5 mmHg (OR = 0.35; 95% CI = 0.19-0.65; p < 0.001), were independent predictors of achieving an optimal hemodynamic response. In the multivariate model, residual MR was not independently associated with optimal hemodynamic response. CONCLUSIONS: Optimal hemodynamic response is achieved in 4 in 10 patients undergoing TEER. AF, higher baseline LAP, and higher postprocedural mitral gradient were negative predictors of optimal hemodynamic response after TEER.

The impact of baseline transmitral diastolic mean gradient on left atrial pressure reduction in patients undergoing transcatheter mitral valve edge-to-edge repair.

BACKGROUND: Elevated transmitral gradient post transcatheter mitral valve edge-to-edge repair (TEER) has been associated with worse outcomes. Whether an elevated baseline transmitral diastolic mean gradient (MG) ≥5 mmHg is associated with hemodynamic outcomes after TEER is unknown. METHODS: A total of 164 consecutive patients undergoing TEER at Mayo Clinic between June 2014 and May 2018 were analyzed in this retrospective study. Baseline demographics, as well as clinical, echocardiographic, and procedural data were obtained. Data on direct left atrial pressure (LAP) before and after TEER were recorded. Logistic regression models were constructed to evaluate the association between preprocedure transmitral diastolic mean gradient (pre-MG) and (1) improvement in LAP following TEER, (2) postprocedure transmitral diastolic mean gradient (post-MG). A decrease in LAP post TEER was considered an improvement in hemodynamic response. Pre-MG was categorized as: ≥5 and <5 mmHg. RESULTS: Median age of the cohort was 81.5 years (Q1: 76.3, Q3: 87) and 34% were female. At baseline, median transmitral diastolic MG was 4 mmHg (Q1: 3, Q3: 5) and median LAP was 19 mmHg (Q1:16, Q3: 23.5). In a multivariable model, adjusted for age and sex, patients with pre-MG ≥ 5 mmHg were less likely to see an improvement in LAP post TEER (adjusted odds ratio [aOR]: 0.22, 95% confidence interval [CI]: 0.09, 0.55; p = 0.001) and more likely to have elevated post-MG (aOR; 7.08, 95% CI: 2.93, 17.13; p < 0.001). CONCLUSION: Higher pre-MG (≥5 mmHg) was associated with a lower reduction in LAP and higher residual transmitral gradient following TEER suggesting other potential contributors to increased LAP besides mitral regurgitation as a cause of elevated baseline MG.

Point of care CYP2C19 genotyping after percutaneous coronary intervention.

Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).

Treatment Effect of Percutaneous Coronary Intervention in Dialysis Patients With ST-Elevation Myocardial Infarction.

RATIONALE & OBJECTIVE: Patients receiving maintenance dialysis have higher mortality after primary percutaneous coronary intervention (pPCI) than patients not receiving dialysis. Whether pPCI confers a benefit to patients receiving dialysis that is similar to that which occurs in lower-risk groups remains unknown. We compared the effect of pPCI on in-hospital outcomes among patients hospitalized for ST-elevation myocardial infarction (STEMI) and receiving maintenance dialysis with the effect among patients hospitalized for STEMI but not receiving dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We used the National Inpatient Sample (2016-2018) and included all adult hospitalizations with a primary diagnosis of STEMI. PREDICTORS: Primary exposure was PCI. Confounders included dialysis status, demographics, insurance, household income, comorbidities, and the elective nature of the admission. OUTCOME: In-hospital mortality, stroke, acute kidney injury, new dialysis requirement, vascular complications, gastrointestinal bleeding, blood transfusion, mechanical ventilation, palliative care, and discharge destination. ANALYTICAL APPROACH: The average treatment effect (ATE) of pPCI was estimated using propensity score matching independently within the group receiving dialysis and the group not receiving dialysis to explore whether the effect is modified by dialysis status. Additionally, the average marginal effect (AME) was calculated accounting for the clustering within hospitals. RESULTS: Among hospitalizations, 4,220 (1.07%) out of 413,500 were for patients receiving dialysis. The dialysis cohort was older (65.2 ± 12.2 vs 63.4 ± 13.1, P < 0.001), had a higher proportion of women (42.4% vs 30.6%, P < 0.001) and more comorbidities, and had a lower proportion of White patients (41.1% vs 71.7%, P < 0.001). Patients receiving dialysis were less likely to undergo angiography (73.1% vs 85.4%, P < 0.001) or pPCI (57.5% vs 79.8%, P < 0.001). Primary PCI was associated with lower mortality in patients receiving dialysis (15.7% vs 27.1%, P < 0.001) as well as in those who were not (5.0% vs 17.4%, P < 0.001). The ATE on mortality did not differ significantly (P interaction = 0.9) between patients receiving dialysis (-8.6% [95% CI, -15.6% to -1.6%], P = 0.02) and those who were not (-8.2% [95% CI, -8.8% to -7.5%], P < 0.001). The AME method showed similar results among patients receiving dialysis (-9.4% [95% CI, -14.8% to -4.0%], P < 0.001) and those who were not (-7.9% [95% CI, -8.5% to -7.4%], P < 0.001) (P interaction = 0.6). Both the ATE and AME were comparable for other in-hospital outcomes in both groups. LIMITATIONS: Administrative data, lack of pharmacotherapy and long-term outcome data, and residual confounding. CONCLUSIONS: Compared with conservative management, pPCI for STEMI was associated with comparable reductions in short-term mortality among patients irrespective of their receipt of maintenance dialysis.

Five-year outcomes of transcatheter mitral valve implantation and redo surgery for mitral prosthesis degeneration.

BACKGROUND: Transcatheter mitral valve replacement (TMVR) has emerged as a feasible alternative to redo surgical mitral valve replacement (SMVR) in patients with degenerated mitral prostheses, with limited comparative data. METHODS: We compared mid-term outcomes in patients with degenerated mitral valve prostheses treated with TMVR or redo SMVR. The primary endpoint was survival at 5 years of follow-up. RESULTS: From 2014 to 2020, 215 patients presented with degenerated mitral valve prostheses. Of whom 86 (40%) were treated with TMVR (75[87%] valve-in-valve and 11[13%] valve-in-ring), while 129 patients (60%) underwent SMVR. The TMVR cohort was older (p < 0.0001), more symptomatic (p = 0.0003) and had more chronic lung disease (p = 0.02), worse renal function (p = 0.02) and higher right ventricular systolic pressures (p < 0.0001). Thirty-day mortality was lower with TMVR versus SMVR (2.4% vs. 10.2%, OR4.69 [95% CI 1.25-30.5], p = 0.04) with probability of mortality at 1, 2, and 5 years being 14.7% versus 17.5%, 24.5% versus 20.7%, and 49.9% versus 34.0%, respectively. Mode of prosthesis degeneration, baseline hemodynamics, and valve selection did not appreciably impact outcomes. CONCLUSIONS: TMVR for degenerated mitral prostheses is associated with better early survival compared to SMVR despite a greater burden of comorbidities. In contrast, 5 year survival rates appear more favorable with SMVR, which may reflect the lower baseline risk of this population. Clinical, hemodynamic, and echocardiographic follow-up support the mid-term durability of TMVR for degenerated mitral prostheses. Further dedicated studies, however, are required to optimize outcomes in this challenging patient cohort and to navigate the choice of approach for each individual patient.

Atrial mitral regurgitation: Characteristics and outcomes of transcatheter mitral valve edge-to-edge repair.

BACKGROUND: Mitral transcatheter edge-to-edge repair (MTEER) is an established therapeutic approach for mitral regurgitation (MR). Functional mitral regurgitation originating from atrial myopathy (A-FMR) has been described. OBJECTIVES: We sought to assess the clinical, echocardiographic and hemodynamic considerations in A-FMR patients undergoing MTEER. METHODS: From 2014 to 2020, patients undergoing MTEER for degenerative MR (DMR), functional MR (FMR), and mixed MR were assessed. A-FMR was defined by the presence of MR > moderate in severity; left ventricular (LV) ejection fraction (LVEF) ≥ 50%; and severe left atrial (LA) enlargement in the absence of LV dysfunction, leaflet pathology, or LV tethering. The diagnosis of A-FMR (vs. ventricular-FMR [V-FMR]) was confirmed by three independent echocardiographers. Baseline characteristics, procedural outcomes as well as clinical and echocardiographic follow-up are reported. Device success was defined as final MR grade ≤ moderate; MR reduction ≥1 grade; and final transmitral gradient <5 mmHg. RESULTS: 306 patients underwent MTEER, including DMR (62%), FMR (19%), and mixed MR (19%). FMR cases included 37 (63.8%) V-FMR and 21 (36.2%) A-FMR. Tricuspid regurgitation (≥ moderate) was higher in A-FMR (80.1%) compared to V-FMR (54%) and DMR (42%). Device success did not significantly differ between A-FMR and V-FMR (57% vs. 73%, p = 0.34) or DMR (57% vs. 64%, p = 1.0). The A-FMR cohort was less likely to achieve ≥3 grades of MR reduction compared to V-FMR (19% vs. 54%, p = 0.01) and DMR (19% vs. 49.7%, p = 0.01). Patients with V-FMR and DMR demonstrated significant reductions in mean left atrial pressure (LAP) and peak LA V-wave, though A-FMR did not (LAP -0.24 ± 4.9, p = 0.83; peak V-wave -1.76 ± 9.1, p = 0.39). In follow-up, echocardiographic and clinical outcomes were similar. CONCLUSIONS: In patients undergoing MTEER, A-FMR represents one-third of FMR cases. A-FMR demonstrates similar procedural success but blunted acute hemodynamic responses compared with DMR and V-FMR following MTEER. Dedicated studies specifically considering A-FMR are needed to discern the optimal therapeutic approaches.

Impact of mitral intervention on outcomes of patients with mitral valve dysfunction and annulus calcification.

OBJECTIVES: To compare all-cause mortality in patients with mitral annulus calcification (MAC) and severe mitral valve dysfunction (MVD) who received standard mitral intervention versus no intervention. BACKGROUND: Patients with MAC often have high surgical risk due to advanced age, comorbidities, and technical challenges related to calcium. The impact of a mitral intervention on outcomes of patients with MAC and severe MVD is not well known. METHODS: Retrospective review of patients with MAC by transthoracic echocardiography (TTE) in 2015 at a single institution. Patients with severe mitral stenosis (MS) or regurgitation (MR) were analyzed and stratified into two groups: surgical or transcatheter intervention performed <1 year after the index TTE, and no or later intervention. The primary endpoint was all-cause mortality. RESULTS: Of 5502 patients with MAC, 357 had severe MVD (MS = 27%, MR = 73%). Of those, 108 underwent mitral intervention (surgery = 87; transcatheter = 21). They were younger (73 ± 11 vs. 76 ± 11 years, p < 0.01) and less frequently had cardiovascular diseases compared with no-intervention. Frequency in women was similar (45% vs. 50%, p = 0.44). During median follow-up of 3.2 years, the intervention group had higher estimated survival than those without intervention (80% vs. 72% at 1 year and 55% vs. 35% at 4 year, p < 0.01). Adjusted for age, eGFR, LVEF < 50%, and pulmonary hypertension, mitral intervention was an independent predictor of lower mortality (hazard ratio = 0.66, 95% confidence interval 0.43-0.99, p = 0.046). CONCLUSION: Patients with MAC and severe MVD who underwent mitral intervention <1 year from index TTE had lower mortality than those without intervention. Mitral intervention was independently associated with lower mortality.

Effect of eliminating pre-discharge transthoracic echocardiogram on outcomes after TAVR.

OBJECTIVES: The aim of this study was to determine the safety of eliminating the pre-discharge transthoracic echocardiogram (TTE) on 30-day outcomes in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: TTE is utilized before, during, and after TAVR. Post-procedural, pre-discharge TTE assists in assessment of prosthesis function and detection of clinically significant paravalvular leak (PVL) after TAVR. METHODS: Patients who underwent TAVR at Mayo Clinic from July 2018 to July 2019 were included in a prospective institutional registry. Patients undergoing TAVR prior to February 2019 received a pre-discharge TTE, while those undergoing TAVR after February 2019 did not. Both cohorts were evaluated with TTE at 30 days post-TAVR. RESULTS: A total of 330 consecutive patients were included. Of these, 160 patients (age 81.1 ± 7.6) had routine pre-discharge TTE, while 170 patients (age 78.9 ± 7.5) were dismissed without routine pre-discharge TTE. Mortality at 30 days was similar between the two groups (0% and 1.2%, respectively). One episode of PVL requiring intervention (0.6%) occurred in the pre-discharge TTE group and none in the group without pre-discharge TTE at 30-day follow-up. There was a similar incidence of total composite primary and secondary adverse events between the cohort receiving a pre-discharge TTE and those without (28.1% vs. 25.3%, P = 0.56) at 30 days. The most common event was need for permanent pacemaker or ICD implantation in both groups (13.1% vs. 11.8%, P = 0.71). CONCLUSIONS: Elimination of the pre-discharge TTE is safe and associated with comparable 30-day outcomes to routine pre-discharge TTE. These findings have implication for TAVR practice cost-efficiency and health care utilization.

Safety and Efficacy of CYP2C19 Genotype-Guided Escalation of P2Y12 Inhibitor Therapy After Percutaneous Coronary Intervention in Chronic Kidney Disease: a Post Hoc Analysis of the TAILOR-PCI Study.

PURPOSE: Chronic kidney disease (CKD) is a risk factor for ischemic and bleeding events with dual antiplatelet therapy after percutaneous coronary intervention (PCI). Whether the presence of CYP2C19 loss of function (LOF) alleles modifies this risk, and whether a genotype-guided (GG) escalation of P2Y12 inhibitor therapy post PCI is safe in this population is unclear. METHODS: This was a post hoc analysis of randomized patients in TAILOR PCI. Patients were divided into two groups based on estimated glomerular filtration rate (eGFR) threshold of < 60 ml/min/1.73 m2 for CKD (n = 539) and non-CKD (n = 4276). The aggregate of cardiovascular death, stroke, myocardial infarction, stent thrombosis, and severe recurrent coronary ischemia at 12-months post-PCI was assessed as the primary endpoint. Secondary endpoint was major or minor bleeding. RESULTS: Mean (standard deviation) eGFR among patients with CKD was 49.5 (8.4) ml/min/1.72 m2. Among all patients, there was no significant interaction between randomized strategy and CKD status for any endpoint. Among LOF carriers, the interaction between randomized strategy and CKD status on composite ischemic outcome was not significant (p = 0.2). GG strategy was not associated with an increased risk of bleeding in either CKD group. CONCLUSIONS: In this exploratory analysis, escalation of P2Y12 inhibitor therapy following a GG strategy did not reduce the primary outcome in CKD. However, P2Y12 inhibitor escalation following a GG strategy was not associated with increased bleeding risk in CKD. Larger studies in CKD are needed. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01742117?term=TAILOR-PCI&draw=2&rank=1 . NCT01742117.

Incidence, Trends, and Outcomes of Type 2 Myocardial Infarction in a Community Cohort.

BACKGROUND: Type 2 myocardial infarction (T2MI) occurs because of an acute imbalance in myocardial oxygen supply and demand in the absence of atherothrombosis. Despite being frequently encountered in clinical practice, the population-based incidence and trends remain unknown, and the long-term outcomes are incompletely characterized. METHODS: We prospectively recruited residents of Olmsted County, Minnesota, who experienced an event associated with a cardiac troponin T >99th percentile of a normal reference population (≥0.01 ng/mL) between January 1, 2003, and December 31, 2012. Events were retrospectively classified into type 1 myocardial infarction (T1MI, atherothombotic event), T2MI, or myocardial injury (troponin rise not meeting criteria for myocardial infarction [MI]) using the universal definition. Outcomes were long-term all-cause and cardiovascular mortality and recurrent MI. T2MI was further subclassified by the inciting event for supply/demand mismatch. RESULTS: A total of 5460 patients had at least one cardiac troponin T ≥0.01 ng/mL; 1365 of these patients were classified as index T1MI (age, 68.5±14.8 years; 63% male) and 1054 were classified as T2MI (age, 73.7±15.8 years; 46% male). The annual incidence of T1MI decreased markedly from 202 to 84 per 100 000 persons between 2003 and 2012 (P<0.001), whereas the incidence of T2MI declined from 130 to 78 per 100 000 persons (P=0.02). In comparison with patients with T1MI, patients with T2MI had higher long-term all-cause mortality after adjustment for age and sex, driven by early and noncardiovascular death. Rates of cardiovascular death were similar after either type of MI (hazard ratio, 0.8 [95% CI, 0.7-1.0], P=0.11). Subclassification of T2MI by cause demonstrated a more favorable prognosis when the principal provoking mechanism was arrhythmia, in comparison with postoperative status, hypotension, anemia, and hypoxia. After index T2MI, the most common MI during follow-up was a recurrent T2MI, whereas the occurrence of a new T1MI was relatively rare (estimated rates at 5 years, 9.7% and 1.7%). CONCLUSIONS: There has been an evolution in the type of MI occurring in the community over a decade, with the incidence of T2MI now being similar to T1MI. Mortality after T2MI is higher and driven by early and noncardiovascular death. The provoking mechanism of supply/demand mismatch affects long-term survival. These findings underscore the healthcare burden of T2MI and provide benchmarks for clinical trial design.

Hemodynamic response to transseptal transcatheter mitral valve replacement in patients with severe mitral stenosis due to severe mitral annular calcification.

OBJECTIVES: We aimed to investigate the invasive hemodynamic changes with transcatheter mitral valve replacement (TMVR) in patients with severe mitral stenosis due to severe mitral annular calcification. BACKGROUND: The hemodynamic response to TMVR in patients with mitral stenosis related to degenerative mitral annular calcification has not been fully elucidated. METHODS: We conducted retrospective review of patients who underwent successful transseptal TMVR with balloon-expandable valves for symptomatic severe mitral stenosis due to mitral annular calcification at our institution between January 2014 and February 2020. Invasive hemodynamic measurements were obtained both before valve implantation (predeployment) and after (postdeployment). RESULTS: Eighteen patients (age 72 ± 10 years, 44% female) were included for the analysis. There was a significant reduction in mean left atrial pressure (23.7 ± 5.6 mmHg versus 20.6 ± 4.8 mmHg; p = .01), left atrial v-wave (mean 39.3 ± 10.2 mmHg versus 32.9 ± 9.9 mmHg; p = .01), and an increase in systemic mean blood pressure (72.6 mmHg ±11.2 versus 79.5 ± 9.9 mmHg; p = .02) postdeployment compared to predeployment. Patients who had symptom improvement at 30-day follow-up tended to have greater reduction in mean left atrial pressure (4.4 ± 4.4 mmHg versus 0.5 ± 5.2 mmHg; p = .16) and v-wave (8.6 ± 9.0 mmHg versus 0.7 ± 8.4 mmHg; p = .10) compared to those who did not experience improvement of symptoms. CONCLUSIONS: Transseptal TMVR for severe mitral stenosis due to mitral annular calcification is associated with reductions in mean left atrial pressure and left atrial v-wave, and an increase in systemic arterial pressure.

Hemolysis after transcatheter mitral valve replacement in degenerated bioprostheses, annuloplasty rings, and mitral annular calcification: Incidence, patient characteristics, and clinical outcomes.

OBJECTIVES: To determine the incidence, characteristics, and outcomes of patients with hemolysis after transcatheter mitral valve replacement (TMVR). BACKGROUND: Hemolysis is an increasingly recognized complication of TMVR. Clinical outcomes and optimal management for patients with hemolysis after TMVR are unclear. METHODS: Patients that underwent mitral valve-in-valve (MViV), valve-in-ring (MViR), and valve-in-mitral annular calcification (ViMAC) at a single center were retrospectively assessed. RESULTS: A total of 101 patients had TMVR, including 69 with MViV, 14 with MViR, and 18 with ViMAC. ViMAC patients had an increased frequency of mild or greater paravalvular leak (PVL) (ViMAC, 72.2%; MViR, 14.3%; MViV, 13.0%; p < .001). Hemolysis occurred in eight patients and was more common after ViMAC (ViMAC, 33.3%; MViR, 7.1%; MViV, 1.5%; p < .001). This required transfusion in five (ViMAC, 4; MViV, 1) and was associated with acute kidney injury in five with ViMAC. Among the ViMAC patients, four had transcatheter re-intervention to treat hemolysis with resolution of anemia in three and mild residual anemia in one with persistent mild PVL. The two ViMAC patients without re-intervention had persistent anemia and died within 6 months. Both MViV and MViR patients with hemolysis did not have PVL but had turbulent flow from left ventricular outflow tract narrowing and their hemolysis was self-limited. CONCLUSIONS: Hemolysis occurs with greater frequency and increased clinical severity after ViMAC as compared to MViV or MViR and is likely related to increased incidence of PVL. These findings demonstrate the need to investigate novel strategies that can reduce the burden of hemolysis with ViMAC.

30-day patient reported outcomes can be predicted by change in left atrial pressure and not change in transmitral gradient following MitraClip.

BACKGROUND: Change in left atrial pressure (LAP) has been shown to be associated with symptom improvement post-MitraClip; however, the association between acute procedural changes in transmitral diastolic mean gradient (MG) compared to LAP and symptom improvement is not well established. METHODS: 164 consecutive patients undergoing MitraClip at Mayo Clinic between June 2014 and May 2018 were included. Preclip and postclip MG and LAP were recorded. Baseline demographics, clinical, and echocardiographic outcomes, including 30-day New York Heart Association (NYHA) functional status were obtained from patient charts. RESULTS: Median age was 81.5 years (IQR: 76.3, 87), 34% were female and 94.5% had NYHA class III and IV functional status at baseline. At baseline, median MG was 4 mmHg (IQR: 3, 5) and LAP was 19 mmHg (IQR: 16, 23.5). Following MitraClip deployment, the median MG was 4 mmHg (IQR: 3, 6) and the median LAP was 17 mmHg (IQR: 14, 21), 69.5% of patients had less than moderate MR. There was no statistically significant association between change in MG and NYHA functional class at 30 days (OR = 0.95, 95% CI: 0.76-1.20). However, a reduction in LAP following MitraClip deployment was significantly associated with improvement in NYHA functional status at 30 days following adjustments for age and sex (aOR 3.36, 95% CI: 1.34-8.65). There was no significant correlation between change in mean LAP and change in MG (p = .98). CONCLUSION: Unlike change in left atrial pressure, change in MG post-MitraClip was not associated with patient reported outcomes at 30 days and did not correlate with change in left atrial pressure. Long-term follow up is needed to evaluate the impact of LA pressure on symptoms.

Diastolic blood pressure predicts outcomes after aortic paravalvular leak closure.

OBJECTIVES: We sought to determine hemodynamic effects of aortic paravalvular leak (PVL) and predictors of clinical outcomes after aortic PVL closure. BACKGROUND: The significance of hemodynamic alterations in PVL and relation to severity, procedural success of percutaneous closure and clinical outcomes have not been defined. METHODS: Patients undergoing percutaneous PVL closure between July 21, 2004 and September 10, 2018 were included. PVL severity was assessed by echocardiography and aortic angiography. Hemodynamics were assessed by intra-arterial pressure tracings before and after PVL closure. The primary outcome was a composite of mortality, redo aortic valve replacement (AVR) and redo PVL closure. RESULTS: One hundred and seventeen patients (mean age 70.3 ± 14.9 years, 79% surgical and 21% transcatheter prostheses) underwent PVL closure with 94% technical success. PVL was moderate or greater in 106 (91%) at baseline and 11 (11%) post-procedure. Diastolic BP for those with moderate or greater PVL was lower than for those with less PVL (50.3 ± 11.7 vs. 56.5 ± 12.4 mmHg, p < .001). Pulse pressure was similar between these groups (69.9 ± 20.3 vs. 67.4 ± 21.2 mmHg, p = .39). 35 patients (34%) had 40 events during a mean follow-up of 1.6 ± 1.9 years (23 deaths, 12 redo AVR, and five redo PVL closures). In a multivariate model, final diastolic BP <47 mmHg (HR 3.27 [1.45-7.36], p = .007) was a significant predictor of the composite endpoint. CONCLUSIONS: Diastolic BP was significantly associated with aortic PVL severity and clinical outcomes after PVL closure. In contrast, pulse pressure did not correlate with PVL severity or outcomes. These findings have implications for clinical management of patients with aortic PVL.

Clinical predictors and impact of postoperative mean gradient on outcome after transcatheter edge-to-edge mitral valve repair.

BACKGROUND: The predictors and clinical significance of increased Doppler-derived mean diastolic gradient (MG) following transcatheter edge-to-edge mitral valve repair (MVTEER) remain controversial. OBJECTIVE: We sought to examine baseline correlates of Doppler-derived increased MG post-MVTEER and its impact on intermediate-term outcomes. METHODS: Patients undergoing MVTEER were analyzed retrospectively. Post-MVTEER increased MG was defined as >5 mmHg or aborted clip implantation due to increased MG intraprocedurally. Baseline MG and 3D-guided mitral valve area (MVA) by planimetry were retrospectively available in 233 and 109 patients. RESULTS: 243 patients were included; 62 (26%) had MG > 5 mmHg post-MVTEER or aborted clip insertion, including 7 (11%) that had aborted clip implantation. Mortality occurred in 63 (26%) during a median follow up of 516 days (IQR 211, 1021). Increased post-MVTEER MG occurred more frequently in females (44% vs. 16%, p < 0.001), those with baseline MVA <4.0 cm2 (71% vs. 16%), baseline MG ≥4 mmHg (61% vs. 20%), or multiple clips implanted (33% vs. 21%, p = 0.04). Increased post-MVTEER MG was associated with increased subsequent mortality compared to those with normal gradient (HR 1.91 95% CI 1.15-3.18 p = 0.016) as was aborted clip insertion compared to all others (HR 5.23 95% CI 2.06-13.28 p < 0.001). CONCLUSIONS: Smaller baseline MVA and increased baseline MG are associated with increased MG post-MVTEER and patients with a Doppler-derived post-MVTEER MG >5 mmHg suffered excess subsequent mortality. In high risk patients considered for MVTEER, identification of those at risk of iatrogenic mitral stenosis with MVTEER is important as they may be optimally treated with alternate surgical or transcatheter therapies.

Effect of a fourth-generation transcatheter valve enhanced skirt on paravalvular leak.

OBJECTIVES: The aim of this study was to assess the 30 day incidence of paravalvular leak (PVL) and need for aortic valve reintervention of a fourth generation balloon expandable transcatheter valve with enhanced skirt (4G-BEV) (SAPIEN 3 Ultra) compared with a third generation balloon expandable transcatheter valve (3G-BEV) (SAPIEN 3). BACKGROUND: The incidence of PVL has steadily declined with iterative improvements in transcatheter aortic valve replacement (TAVR) technology and implantation strategies. METHODS: Patients who underwent TAVR at Mayo Clinic from 7/2018 to 7/2019 were included in a prospective institutional registry. 4G-BEV has been utilized since 2/2019, and, after this date, 3G-BEV and 4G-BEV were simultaneously used. 4G-BEV had three sizes (20, 23, and 26 mm) while 3G-BEV included four sizes (20, 23, 26, and 29 mm). Both cohorts were evaluated at 30 days post-TAVR with a transthoracic echocardiogram to assess for PVL. RESULTS: A total of 260 consecutive patients were included. Of these, 101 patients received a 4G-BEV and 159 patients received a 3G-BEV. There were more females (p = .0005) and a lower aortic valve calcium score (p = .02) in the 4G-BEV cohort at baseline. Age, STS risk score, NYHA Class, and aortic valve mean gradient did not differ between groups. 4G-BEV was associated with a lower incidence of mild PVL (10.8 vs. 36.5%; p < .0001) and moderate PVL (0 vs. 5.8%) compared to the 3G-BEV at 30 days. There was no association between PVL and valve size in either cohort. CONCLUSIONS: Utilization of 4G-BEV is associated with reduced PVL at 30 days post-TAVR compared with 3G-BEV.

Next-Generation Sequencing of CYP2C19 in Stent Thrombosis: Implications for Clopidogrel Pharmacogenomics.

PURPOSE: Describe CYP2C19 sequencing results in the largest series of clopidogrel-treated cases with stent thrombosis (ST), the closest clinical phenotype to clopidogrel resistance. Evaluate the impact of CYP2C19 genetic variation detected by next-generation sequencing (NGS) with comprehensive annotation and functional studies. METHODS: Seventy ST cases on clopidogrel identified from the PLATO trial (n = 58) and Mayo Clinic biorepository (n = 12) were matched 1:1 with controls for age, race, sex, diabetes mellitus, presentation, and stent type. NGS was performed to cover the entire CYP2C19 gene. Assessment of exonic variants involved measuring in vitro protein expression levels. Intronic variants were evaluated for potential splicing motif variations. RESULTS: Poor metabolizers (n = 4) and rare CYP2C19*8, CYP2C19*15, and CYP2C19*11 alleles were identified only in ST cases. CYP2C19*17 heterozygote carriers were observed more frequently in cases (n = 29) than controls (n = 18). Functional studies of CYP2C19 exonic variants (n = 11) revealed 3 cases and only 1 control carrying a deleterious variant as determined by in vitro protein expression studies. Greater intronic variation unique to ST cases (n = 169) compared with controls (n = 84) was observed with predictions revealing 13 allele candidates that may lead to a potential disruption of splicing and a loss-of-function effect of CYP2C19 in ST cases. CONCLUSION: NGS detected CYP2C19 poor metabolizers and paradoxically greater number of so-called rapid metabolizers in ST cases. Rare deleterious exonic variation occurs in 4%, and potentially disruptive intronic alleles occur in 16% of ST cases. Additional studies are required to evaluate the role of these variants in platelet aggregation and clopidogrel metabolism.

Antegrade transseptal transcatheter aortic valve replacement: Back to the future?

Antegrade transseptal approach was utilized in the first human case of transcatheter aortic valve replacement (TAVR) and in the early phase of TAVR. Various challenges with the antegrade transseptal approach including procedural complexity, need for atrial septal crossing, and potential for injury to the mitral valve apparatus led it to being supplanted by other approaches. These challenges have now largely been mitigated as structural interventionalists routinely perform left atrial procedures. We report a case of antegrade transseptal TAVR using a large bore sheath placed in the mid left ventricle across the mitral orifice to protect the mitral valve apparatus and facilitate valve deployment. An 84-year-old man with heart failure symptoms was seen for severe aortic stenosis. The severity of peripheral arterial disease precluded femoral, axillary, carotid, or transcaval routes. After transseptal puncture and creation of an arteriovenous rail, a long 26-Fr sheath was advanced from the right femoral vein transseptally over the arteriovenous rail, past the mitral valve inflow to the mid left ventricular cavity. The sheath provided a stable platform with stable intraprocedure hemodynamics. Balloon valvuloplasty was performed in an antegrade manner, after which a 29-mm SAPIEN S3 prosthesis was advanced into the aortic valve position and deployed under rapid pacing. We observed no injury to the mitral leaflets or subvalvular apparatus after the procedure. The antegrade transseptal approach should be revisited as an option for patients at high surgical risk with no other suitable access site. The use of a large bore sheath facilitates this approach.